The present invention relates to new substituted phthalides, to a process for their preparation and to pharmaceutical compositions containing them.
Epilepsy is a collective term used to describe a group of chronic convulsive disorders having in common the occurrence of brief episodes (seizures) associated with loss or disturbance of consciousness. There are many anti-epilepsy drugs available in clinical applications, such as Phenobarbital, Phenytoin, Zolenzepine, Ethosuximide, Paramethadione, Valproic acid. Although these medicines are able to protect patients from convulsion of various epilepsies to different extents, adverse effects and tolerance usually prevent long-term therapy. New compounds with novel structural features and with new mechanisms of action are needed in order to improve the therapeutic effect and eliminate or reduce the adverse response.
The compounds of the present invention are new, devoid of any toxicity and exhibit interesting pharmacological properties as anti-convulsants. Furthermore, they are potent calcium and sodium channel blockers conferring on them neuroprotective and cognition-enhancing properties.
More specifically, the present invention relates to compounds of formula (I): 
wherein:
R1 represents a linear or branched (C1-C12)alkyl group or a ureido group,
R2 represents a hydrogen atom or a linear or branched (C1-C12)alkyl group,
or R1 and R2, together with the carbon atom carrying them, form a cycloalkyl group containing 5 or 6 carbon atoms,
R3 represents a group CN, NO2, NRaRxe2x80x2a, NRaSO2Rxe2x80x2a, NRaCZR5 or CZNRaRxe2x80x2a wherein Z represents an oxygen or sulphur atom and R5 represents a group ORa, Ra or NRaRxe2x80x2a (wherein Ra and Rxe2x80x2a, which may be the same or different, represent a hydrogen atom or a linear or branched (C1-C6)alkyl group, a (C3-C8)cycloalkyl group, a (C3-C8)cycloalkyl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, a phenyl group or a phenyl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched),
R4 represents a hydrogen atom or a group R3 as defined hereinbefore,
it being understood that:
the phenyl or phenylalkyl groups may be substituted on the benzene ring by one or more substituents selected from linear or branched (C1-C6)alkyl, hydroxy, linear or branched (C1-C6)alkoxy, amino, linear or branched (C1-C6)alkylamino, di-(C1-C6)alkylamino in which each allyl moiety is linear or branched, NO2 and halogen atoms,
the alkyl group may be substituted by one or more substituents selected from hydroxy, carboxy, linear or branched (C1-C6)alkyl, linear or branched (C1-C6)alkoxy and halogen atoms,
the cycloalkyl and cycloalkylalkyl groups may be substituted on the cyclic moiety by one or more substituents selected from hydroxy, carboxy, linear or branched (C1-C6)alkoxy and halogen atoms,
and provided that the compound of formula (I) cannot represent 3-methyl-, 3-ethyl-, 3,3-diethyl- or 3,3-diethyl-6-nitro-phthalide or 3-methyl- or 3,3-dimethyl-6-amino-phthalide or 3,3-dimethyl-6-(dimethylamino)-phthalide, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
Among the pharmaceutically acceptable acids there may be mentioned, without implying any limitation, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, methanesulphonic acid, camphoric acid, oxalic acid etc.
Among the pharmaceutically acceptable bases there may be mentioned, without implying any limitation, sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine etc.
Preferred compounds of the invention are compounds of formula (I) wherein R4 represents a hydrogen atom.
The group R1 is preferably a linear or branched (C1-C12)alkyl group and, more especially, the groups methyl, ethyl and n-butyl, or R1 and R2, together with the carbon atom carrying them, form a ring having 5 or 6 carbon atoms.
Advantageously, the invention relates to compounds of formula (I) wherein R3 represents a nitro group or a group NRaRxe2x80x2a (wherein Ra and Rxe2x80x2a are as defined hereinbefore) such as, for example, the groups amino, formamido, isopropylanino or dimethylamino.
Even more preferably, the invention relates to compounds of formula (I) that are:
6-amino-3-butyl-phthalide,
(+)-(3R)-6-amino-3-butyl-phthalide,
3-butyl-6-isopropylamino-phthalide,
6-amino-3,3-spiro-tetramethylene-phthalide,
3-butyl-6-formamido-phthalide,
6-amino-3,3-diethyl-phthalide.
The enantiomers and diastereoisomers, as well as the addition salts with a pharmaceutically acceptable acid or base, of the preferred compounds of the invention form an integral part of the invention.
The invention relates also to a process for the preparation of compounds of formula (I), which process is characterised in that there is used as starting material a compound of formula (II): 
wherein R1 and R2 are as defined hereinbefore,
which is nitrated under conditions of electrophilic substitution to yield the compound of formula (I/a), a particular case of the compounds of formula (I): 
wherein R1 and R2 are as defined hereinbefore,
which may be hydrogenated chemically or by means of catalytic hydrogenation to obtain the compound of formula (I/b), a particular case of the compounds of formula (I): 
wherein R1 and R2 are as defined hereinbefore,
which may be:
either subjected to the action of one or two molecules of a compound of formula (III):
R1axe2x88x92Xxe2x80x83xe2x80x83(III)
wherein R1a may take any of the meanings of Ra except for a hydrogen atom and X represents a leaving group such as a halogen atom or a tosyl group, to yield the compound of formula (I/c), a particular case of the compounds of formula (I): 
wherein R1, R2, Ra and R1a are as defined hereinbefore,
or subjected to the action of a compound of formula (IV): 
wherein Z is as defined hereinbefore and Rxe2x80x25 represents a group Ra or ORa (wherein Ra is as defined hereinbefore),
to obtain the compound of formula (I/d), a particular case of the compounds of formula (I): 
wherein R1, R2, Z and Rxe2x80x25 are as defined hereinbefore,
which may be subjected to the action of a compound of formula (III) to yield the compound of formula (I/e), a particular case of the compounds of formula (I): 
wherein R1, R2, R5, Rxe2x80x25 and Z are as defined hereinbefore,
or subjected to the action of a compound of formula (V):
Zxe2x95x90Cxe2x95x90Nxe2x80x94Raxe2x80x83xe2x80x83(V)
wherein Z and Ra are as defined hereinbefore, to obtain the compound of formula (I/f), a particular case of the compounds of formula (I): 
wherein R1, R2, Z and Ra are as defined hereinbefore,
which may be subjected to the action of a compound of formula (III) to yield the compound of formula (I/g), a particular case of the compounds of formula (I): 
wherein R1, R2, Ra, Rxe2x80x2a, R1a and Z are as defined hereinbefore,
or subjected to the successive action of nitrous acid and then CuCN to yield the compound of formula (I/h), a particular case of the compounds of formula (I): 
wherein R1 and R2 are as defined hereinbefore,
which may be hydrolysed in an acid or basic medium to yield the compound of formula (I/i), a particular case of the compounds of formula (I): 
wherein R1 and R2 are as defined hereinbefore,
which may be subjected to the action of a compound of formula (III) to obtain the compound of formula (I/j), a particular case of the compounds of formula (I): 
wherein R1, R2, Ra and R1a are as defined hereinbefore,
which compounds of formulae (I/i) and (I/j) may be subjected to the action of a thionating agent such as Lawesson""s reagent to yield the compound of formula (I/k), a particular case of the compounds of formula (I): 
wherein R1, R2, Ra and Rxe2x80x2a are as defined hereinbefore,
which compounds of formulae (I/a) to (I/k) may be subjected to a second nitration and optionally also to the entire sequence of reactions described hereinbefore to obtain the compound of formula (I/l), a particular case of the compounds of formula (I): 
wherein R1, R2 and R3 are as defined hereinbefore and Rxe2x80x24 may take any of the meanings of the group R3,
the compounds of formulae (I/a) to (I/l) constituting the totality of the compounds of formula (I), which may be purified according to a conventional separation technique, are converted, if desired, into their addition salts with a pharmaceutically acceptable acid or base and are separated, where appropriate, into their isomers according to a conventional separation technique.
The compounds of formula (II) are either commercially available or readily accessible to the person skilled in the art by means of conventional chemical reactions.
In particular, compounds of formula (II) may be obtained:
starting from 2-formyl-benzoic acid, which is condensed with one or two molecules of Grignard reagents RMgXxe2x80x2 wherein R represents a linear or branched (C1-C12)alkyl group and Xxe2x80x2 represents a halogen atom,
or starting from phthalic anhydride, which is condensed with:
a compound of formula RCOCl or the corresponding anhydride (wherein R is as defined hereinbefore), followed by catalytic or chemical hydrogenation,
or a compound of formula Xxe2x80x2xe2x80x94Mgxe2x80x94(CH2)nxe2x80x94Mgxe2x80x94Xxe2x80x2 wherein Xxe2x80x2 is as defined hereinbefore and n is 4 or 5.
In addition to the fact that the compounds of the present invention are new, they exhibit very interesting pharmacological properties and are devoid of any toxicity.
They have anti-convulsant properties rendering them of use as anti-epileptic compounds. Results have shown that they are new calcium antagonists and can be used as a basis for elucidating the anti-epileptic mechanism.
Compounds of the invention furthermore exhibit potent neuroprotective effects and cognition-enhancing properties rendering them of use in:
the treatment of cognitive deficiencies associated with ageing and with neurodegenerative disease such as Alzheimer""s disease, Parkinson""s disease, Pick""s disease, Korsakoff""s disease and frontal lobe and subcortical dementias,
the prophylactic treatment of chronic neurodegenerative diseases,
and in the prevention of recurrence of cerebral ischemia
The invention relates also to pharmaceutical compositions comprising as active ingredient at least one compound of formula (I) together with one or more appropriate, inert, non-toxic excipients. Among the pharmaceutical compositions according to the invention there may be mentioned more especially those that are suitable for oral parenteral (intravenous or subcutaneous) and nasal administration, tablets or sugar coated tablets, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable preparations, drinkable suspensions etc.
The dosage used can be adapted to the nature and the severity of the disorder, the administration route and the age and weight of the patient The dosage varies from 0.01 mg to 1 g per day in one or more administrations.
The following Examples illustrate the invention but do not limit it in any way.
The following Preparations yield compounds of the invention or synthesis intermediates that are useful in the preparation of compounds of the invention.
Preparation 1: 3-Butylphthalide
A dry three-necked flask is charged with 16.0 g (0.658 mol) of magnesium turnings, which are covered with anhydrous ether. A small portion of n-butyl bromide is added dropwise to the mixture to initiate the reaction. The addition of n-butyl bromide is continued until the magnesium turnings are digested completely; the total amount of n-butyl bromide added is 82 g (0.599 mol). The reaction mixture is then heated under reflux for 1 hour. To the cooled Grignard reagent there is added, dropwise, a solution of 36.0 g (0.24 mol) of o-phthalaldehydic acid in 200 ml of anhydrous tetrahydrofuran in 1 hour. The reaction mixture is refluxed for 1 hour and cooled. To this mixture there are carefully added 250 ml of saturated ammonium chloride solution. Concentrated hydrochloric acid is added to make the mixture pH=2. The ethereal phase is separated off and the aqueous phase is extracted three times with ether. The combined organic phase is dried over sodium sulphate and evaporated. The residue is distilled in vacuo to give the title compound.
Boiling point: 144-148xc2x0 C./2 mmHg.
Preparation 2: 3-Ethylphthalide
Analogously to the method described in Preparation 1, reaction of 30 g (0.20 mol) of o-phthalaldehydic acid, 65.38 g (0.60 mol) of ethyl bromide and 16.0 g (0.66 mol) of magnesium turnings is carried out to give the title compound.
Boiling point: 110-125xc2x0 C./2 mmHg; Elemental microanalysis:
Preparation 3: 3-Hexylphthalide
Analogously to the method described in Preparation 1, reaction of 8.6 g (0.0573 mol) of phthalaldehydic acid, 28.4 g (0.172 mol) of n-hexyl bromide and 4.6 g (0.189 mol) of magnesium turnings is carried out to give the title compound.
Boiling point: 182-185xc2x0 C./4 mmHg; Elemental microanalysis:
Preparation 4: 3-Octylphthalide
Analogously to the method described in Preparation 1, reaction of 10 g (0.067 mol) of o-phthalaldehydic acid, 38.8 g (0.201 mol) of n-octyl chloride and 5.3 g (0.221 mol) of magnesium turnings is carried out to give the title compound.
Boiling point: 174-180xc2x0 C./2 mmHg; Elemental microanalysis:
Preparation 5: 3,3-Diethylphthalide
3.6 g (0.15 mol) of magnesium turnings are reacted with 15.26 g (0.14 mol) of ethyl bromide in anhydrous ether to make the Grignard reagent, to which there is added, dropwise, a solution of 10.0 g (0.068 mol) of phthalic anhydride in anhydrous THF. After completing the addition, the reaction mixture is refluxed for 2 hours. To the cooling mixture there is added a saturated solution of ammonium chloride and the mixture is acidified with concentrated hydrochloric acid. The acidified liquid is extracted several times with ether. The combined organic phase is washed with water and dried over sodium sulphate. The solvent is removed and the residue is crystallised from petroleum ether to give 4.5 g of the title compound.
Boiling point: 110-125xc2x0 C./2 mmHg; Elemental microanalysis:
Preparation 6: 3,3-Spiro-tetramethylenephthalide
Analogously to the method described in Preparation 5, reaction of 5.4 g (0.22 mol) of magnesium turnings, 21.6 g (0.10 mol) of 1,4-dibromobutane and 15.0 g (0.101 mol) of phthalic anhydride is carried out to give the title compound.
Boiling point: 130-154xc2x0 C./7 mmHg.
The solidified compound is crystallised from ethanol.
Melting point: 74-75xc2x0 C.; Elemental microanalysis:
Preparation 7: 3,3-Spiro-pentamethylenephthalide
Analogous to the method described in Preparation 6, using 1,5-dibromopentane.